Dendritic cells (DC) are the most efficient antigen presenting cells (APC) and have been successfully used to induce immune responses to tumors, viruses and alloantigens. On the other hand, some subsets of DC, either from thymus or spleen, have been shown to have tolerogenic potential in several models including transplantation as well as autoimmunity. We have evaluated the murine model of insulin dependent diabetes mellitus (IDDM), the non-obese diabetic (NOD) mouse, as a means to explore the role of DC in the therapy of autoimmune disease. This model allows the assessment of DC-based therapy both during the period of insulitis and in a transplant setting following the onset of diabetes. Many of the islet cell antigens that contribute to the development of diabetes have been identified and some of them have been used to prevent the induction of diabetes. The combination of some of these antigens with DC with tolerogenic potential should prove to be a powerful way to induce specific tolerance that leads to protection against the development of diabetes. Preliminary data that we have obtained suggests that NOD DC function normally, and demonstrates that we are able to generate both stimulatory and tolerogenic DC from these mice. In vivo therapy of young NOD mice with tolerogenic DC pulsed with peptides derived from islet cell antigens resulted in prevention of diabetes induction, suggesting that this therapeutic has promise. In this proposal we plan to test the hypothesis that tolerogenic DC can prevent and/or cure diabetes in the NOD mouse via their ability to induce the development of an immunoregulatory Th2 response. The overall aim of the work proposed will be to test this hypothesis and, in particular, explore the role of subsets of DC in determining either the development of autoimmunity or prevention of the onset of autoimmune disease in vivo. The specific aim of this proposal are: 1) To demonstrate the therapeutic potential of DC subsets to prevent insulitis and diabetes. 2) To demonstrate the therapeutic potential of DC during the development of diabetes. 3) To demonstrate the ability of DC to induce tolerance to islet allografts in diabetic NOD mice. The overall aim of the work proposed will be to test this hypothesis and to explore the role of subsets of DC in determining either the development of autoimmunity or prevention of the onset of autoimmune disease in vivo.